text: Antisense oligonucleotides (ASOs) are single-stranded DNA molecules with full complementarity to one select target mRNA and may act by blocking protein translation (via steric hindrance), causing mRNA degradation (via RNase H-cleavage) or changing pre-mRNA splicing. These short oligonucleotides have already been approved by the FDA for ten genetic disorders and many are currently in the pipeline to be approved/tested. Using oligonucleotide technology, we are now able to control protein expression via RNA interference, and are able to affect previously defined “undruggable” proteins. Even though this therapy has a lot of promise and potential, it comes with many limitations.
  Compared to siRNA and microRNA, ASOs are more versatile in reducing protein expression, they have the ability to also enhance target translation. ASOs can also be customized with ease and accuracy, allowing for the targeting of virtually any mutated gene. This allows for a greater level of application in the field of precision and personalized medicine.
  The main challenge of ASO therapies to specific tissues and cellular uptake is what poses a great challenge and limitation. Liposomal delivery is one such way to overcome such issues. Liposomal delivery system comes with its own share of limitations. Serum proteins in the bloodstream destabilize the lipoprotein. This destabilization leads to the depletion of protein and exposing cargo to the unstable environment. This hindrance can be overcome by using PEGs (poly(ethylene glycol) . However, PEGs are not biodegradable causing them to accumulate within the body leading to adverse effects and causing hypersensitivity. In addition, multiple rounds of therapy with PEGs can lead to the formation of PEG antibodies, which can lead to lack of efficiency in preventing the rupture of the liposome that it is attached to.
  Using immunoliposomes it has been shown that targeting can be more specific as by using antibody’s specific to the protein of expression in that area, it results in the ASO drug directly impact the target site and nowhere else. Moreover, immunoliposomes are slow to dissociate leading to precise release of the ASO drug which they encapsulate.